3,4-Disubstituted oxetan-2-ones are important intermediates for the preparation of pharmacologically interesting .beta.-lactones, in particular of the enzyme inhibitors lipstatin, tetrahydrolipstatin, esterastin, tetrahydroesterastin, valilactone, panclicin D and structurally related compounds.
Concerning the number of reaction steps, the required starting materials and reagents, the necessary purification steps and/or the overall yield, the hitherto known procedures used for the preparation of these 3,4-disubstituted oxetan-2-ones as enantiomerically and diastereomerically pure compounds are not satisfactory.
The procedure of Barbier, Schneider, and Widmer (P. Barbier, F. Schneider, U. Widmer, Helv. Chim. Acta 1987, 70, 1412-1418) for the synthesis of (3S,4S)-3-hexyl-4-(2R)-2hydroxytridecyl!oxetan-2-one starting from methyl (R)-3-hydroxytetradecanoate affords after six reaction steps an overall yield of 6%.
The procedure of Pommier, Pons, Kocienski, and Wong (A. Pommier, J.-M. Pons, P. J. Kocienski, L. Wong, Synthesis 1994, 1294-1300) for the synthesis of the same oxetan-2-one starting from methyl (R)-3-hydroxytetradecanoate affords after five reaction steps an overall yield of 40%. However, there have to be considered three additional steps at the beginning of the synthesis for the preparation of 3-hexyl-3-trimethylsilylketen.
The procedure of Uskokovic et al. (N. K. Chadha, A. D. Batcho, P. C. Tang, L. F. Courtney, C. M. Cook, P. M. Wovkulich, M. R. Uskokovic, J. Org. Chem. 1991, 56, 4714-4718) for the synthesis of (3S,4S)-3-hexyl-4-(2S)-2-hydroxytridecyl!oxetan-2-one (Formula XI) starting from cyclopentadien affords in 17 steps an overall yield of only 1%.
The procedure of Hanessian, Tehim, and Chen (S. Hanessian, A. Tehim, P. Chen, J. Org. Chem. 1993, 58, 7768-7781) for the synthesis of (3S,4S)-3-hexyl-4-(2S)-2-hydroxytridecyl!oxetan-2-one (Formula XI) starting from dodecanal affords in 9 steps an overall yield of 35%.
The procedure of Fleming and Lawrence (I. Fleming, N. J. Lawrence, Tetrahedron Lett. 1990, 31, 3645-3648) for (3S,4S)-3-hexyl-4-(2S)-2-hydroxytridecyl!oxetan-2-one (Formula XI) starting from 3-(dimethylphenylsilyl)propynoic acid affords in 19 steps an overall yield of 10%.
The procedures for the conversion of 2,5-disubstituted .beta.-hydroxy-.delta.-lactones into the corresponding 3,4-disubstituted oxetan-2-ones according to Ramig et al. (J. J. Landi, L. M. Garofalo, K. Ramig, Tetrahedon Lett. 1993, 34, 277-280), Karpf and Zutter (M. Karpf, U. Zutter, European Patent Application 0 443 449 A2, 15.02.1991/28.08.1991), and Barbier and Schneider (P. Barbier, F. Schneider, J. Org. Chem. 1988, 53, 1218-1221) are characterized by a high number of reaction steps and consequently by a low overall yield.
The present invention resulted from the intention to develop an efficient procedure for the preparation of oxetan-2-ones for enzyme inhibitors and related compounds with a .beta.-lactone moiety via new intermediates. This procedure should be characterized by a smaller number of reaction steps, the use of easy to introduce and easy to cleave inexpensive protecting groups, and an efficient separation of diastereoisomers.